PAPASH , Ps APASH and PASS autoinflammatory syndromes: phenotypic heterogeneity, common biological signature and response to immunosuppressive regimens

Dear Editor, Hidradenitis suppurativa (HS) (also known as suppurative hidradenitis) is a chronic inflammatory disease of skin appendages, commonly associating with other conditions including spondyloarthritis,1 2 and is a major component of severe cutaneo‐articular autoinflammatory syndromes (AIS), called PAPASH [Pyogenic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis], PsAPASH (PSoriatic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis) and PASS (Pyoderma gangrenosum, Acne, Suppurative hidradenitis and ankylosing Spondylitis).1 3 The clinical phenotypes of these AIS are ill‐defined, and unlike PASH (Pyoderma gangrenosum, Acne, Suppurative Hidradenitis) or PAPA (Pyogenic Arthritis, Pyoderma gangrenosum, Acne) syndromes, still lack any biological or genetic marker. Moreover, their optimal therapeutic management remains unclear.4 5 We report an in‐depth description of the clinicopathological, radiological, immunobiological features and treatment outcomes in a series of nine patients diagnosed with PAPASH (n = 2), PsAPASH (n = 1) or PASS (n = 6), in three tertiary care centres between 2014 and 2016. The main patients characteristics are listed in Table 1. Mean age at onset of skin and/or joint symptoms was 24·4 years (range 14–40 years) and HS, graded as Hurley stage 3 in all but one case, was the initial component at syndrome onset in six patients. Three patients had severe inguinoperineal and gluteal lesions [latent class (LC)3 HS phenotype], while another three patients also presented features of the LC1 and LC2 phenotypes, notably nodular acne‐like lesions of face and back, and the final three had concurrent acne keloidalis nuchae and aseptic folliculitis.6 Two patients had a family history of HS. Diagnosis of pyoderma gangrenosum was based on clinicopathological findings, according to the 2018 Delphi Consensus of International Experts. HS preceded pyoderma gangrenosum onset in three cases, with a mean time interval of 17 years (range 15–20 years), and was concomitant in the other five patients. Seven patients were diagnosed with spondyloarthritis, either axial (n = 3), undifferentiated (n = 3) or psoriatic (n = 1), and the other two were diagnosed with undifferentiated poly/oligoarthritis. Onset of joint symptoms preceded skin signs in two cases, and was concomitant or within the same year in three cases. Clinical characteristics of the nine patients with imaging and pathological data ACPA; anticitrullinated protein antibody; GI, gastrointestinal; HLA, human leucocyte antigen; HS, hidradenitis suppurativa; MRI: magnetic resonance imaging; MTX, methotrexate; NA, not available; ND, neutrophilic dermatosis; NSAID, nonsteroidal anti‐inflammatory drug; PAPASH, Pyogenic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis; PASS, Pyoderma gangrenosum, Acne, Suppurative hidradenitis and ankylosing Spondylitis; PsAPASH, PSoriatic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis; PG, pyoderma gangrenosum; RF, rheumatoid factor; SIJ, sacroiliac joint. Clinical characteristics of the nine patients with imaging and pathological data ACPA; anticitrullinated protein antibody; GI, gastrointestinal; HLA, human leucocyte antigen; HS, hidradenitis suppurativa; MRI: magnetic resonance imaging; MTX, methotrexate; NA, not available; ND, neutrophilic dermatosis; NSAID, nonsteroidal anti‐inflammatory drug; PAPASH, Pyogenic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis; PASS, Pyoderma gangrenosum, Acne, Suppurative hidradenitis and ankylosing Spondylitis; PsAPASH, PSoriatic Arthritis, Pyoderma gangrenosum, Acne, Suppurative Hidradenitis; PG, pyoderma gangrenosum; RF, rheumatoid factor; SIJ, sacroiliac joint. Although none of the patients reported any gastrointestinal symptoms, endoscopy was performed to exclude an underlying inflammatory bowel disease (IBD) in patients with major asthenia, anaemia and high (CRP) C‐reactive protein serum level; this was done for five patients, with macroscopically normal results. However, after blinded interpretation by two independent experts, pathology revealed areas of destruction of the focal antric glands with mild neutrophil cell infiltrate in Patient 1, and mild to moderate colon changes evoking subclinical IBD in Patient 2. Finally, a fundus biopsy in Patient 9 showed an intense chorionic neutrophilic infiltrate associated with cryptic epithelial cell necrosis and fake membranes. The remaining cases were considered normal. Most patients had high CRP (mean: 68 mg L−1; normal < 5 mg L‐1), which correlated with increased serum amyloid A levels in four of six patients analysed, and five showed polyclonal hypergammaglobulinaemia. Seven out of eight patients had positive serological detection for anti‐Saccharomyces cerevisiae antibodies (ASCA) using D‐Tek Kit (Bluewell IgA‐IgG Screen ELISA; ASCC02‐96; Diagnostic Technology, Mons, Belgium), with high IgG titres in three. The genetic status of candidate genes was also checked in all cases after written informed consent was obtained from participants. DNA was extracted from patient blood leucocytes and amplified by PCR using specific primers of all exons and at least 100 base pairs of flanking intronic sequences. Sequencing of the gamma‐secretase complex genes PSENEN (NM_001281532), PSEN1 (NC_000014), NCSTN (NM_015331) and APH1 (NM_016022), as well as PSTPIP1 (NC_000015) and NOD2 (NC_000016), did not reveal any mutation, supporting alternative immunogenetic scenarios to those identified in other AIS including PASH7 and PAPA.8 Regarding treatment outcomes, patients went through numerous treatment lines, including primary use of antibiotics, with poor impact on HS; retinoids and dapsone were used as second‐line treatments in four cases. Conventional immunosuppressants methotrexate, steroids, azathioprine and ciclosporin also failed when used alone. The tumour necrosis factor‐α (TNF‐α) antagonists adalimumab (four patients) and infliximab (four patients) were the most effective therapies, allowing complete or partial control of skin and systemic components in eight of nine patients, although they required the use of high‐dose regimens (adalimumab 40 mg weekly after loading doses or infliximab up to 10 mg kg‐1 every 4 weeks) in six patients, and/or combination with immunosuppressants (methotrexate, oral steroids or sirolimus) in five patients. Complete control of joint disease was obtained in all cases. Anakinra 100 mg daily, ustekinumab and tocilizumab were ineffective for both cutaneous and rheumatological symptoms in Patient 1. In conclusion, the present data indicate that despite phenotypic heterogeneity, the AIS PAPASH, PsAPASH and PASS share (i) similar skin features with severe HS, mainly the LC3 phenotype, in nonsmoking and nonoverweight patients, (ii) the presence of ASCA as a common biological signature which, together with (iii) evidence of subclinical digestive tract inflammation and refractory course under immunosuppressive therapies, raise the contribution of underlying digestive dysbiosis with as yet unidentified genetic factors, leading to dysregulated skin, joint and systemic innate immune responses. Funding sources: this work was supported by the Société Française de Dermatologie Conflicts of interest: H.B. had paid activities as consultant, adviser or speaker for AbbVie, Almirall, Amgen, Boehringer‐Ingelheim, Celgene, Janssen, Leo Pharma, Lilly, Mylan, Novartis, Pfizer, Sun Pharmaceuticals and UCB, and received grant support from Pfizer. P.C. had paid activities as consultant, adviser or speaker for Pfizer, AbbVie, Bristol‐Myers Squibb, MSD, Janssen, Novartis, Celgene, Roche‐Chugai and UCB (< USD10 000 each) and has been an investigator for Roche‐Chugai, Sanofi Aventis, AbbVie, Pfizer, Celgene, UCB, and BMS. P.R. had paid activities as consultant, adviser or speaker for AstraZeneca, Grunenthal, Ipsen/Menarini, Savient, and UCB.